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Regulatory T cells (CD4+CD25brightFoxP3+) expansion in systemic sclerosis correlates with disease activity and severity

https://doi.org/10.1016/j.cellimm.2009.12.009Get rights and content

Abstract

Background

The role and function of T regulatory (Treg) cells have not been fully investigated in patients with systemic sclerosis (SSc).

Methods

Ten patients with SSc donated 20 ml of peripheral blood. Activity (Valentini) and severity (Medsger) scores for SSc were calculated for all patients. Healthy volunteers (controls) were matched to each patient by gender and age. CD4+ cells were separated using the MACS system. The numbers of Treg cells were estimated by flow cytometry after staining for CD4, CD25, and FoxP3 and calculated as patient-to-control ratio separately for each experiment. Correlations with activity and severity indices of the disease were performed. Twenty-four-hour production of TGF-β and IL-10 by activated CD4+ cells was measured by ELISA in culture supernatants.

Results

The numbers of Treg cells, expressed as patient-to-control ratio, correlated significantly with both activity and severity indices (r = 0.71, p = 0.034 and r = 0.67, p = 0.044, respectively). ELISA-measured production of TGF-β and IL-10 by CD4+ cells was similar in patients and controls.

Conclusions

Increased numbers of Treg cells are present in patients with SSc, correlating with activity and severity of the disease. This expansion of Treg cells was not accompanied, however, by heightened TGF-β or IL-10 production. Further studies to elaborate the causes and functional significance of Treg cell expansion in SSc are needed.

Introduction

Regulatory T (Treg) cells play a critical role in maintenance of immunologic self-tolerance as well as regulation of immune responses. Decreased numbers and/or defective suppressive function of Treg cells have been reported in patients with a variety of autoimmune and allergic disorders [1]. In systemic lupus erythematosus or rheumatoid arthritis, for example, Treg cell dysfunction is believed to contribute to mechanisms of initiation and/or maintenance of high disease activity [2], [3], [4].

Systemic sclerosis (SSc) represents one of the autoimmune disorders where the role and function of Treg cells may be of particular interest because of the tight involvement of tissue growth factor beta (TGF-β) in both the pathogenesis of SSc and immunobiology of Treg cells, as TGF-β is vital to their development, survival and activity [5], [6], [7].

Some studies have demonstrated increased, not decreased, percentages of CD4+CD25+ cells in peripheral blood of patients with SSc [8], [9]. One recent study confirmed the existence expanded pool of true CD4+CD25bright FoxP3+ Treg cells in patients with SSc [10]. However, the relationship of Treg cells numbers to the activity or severity of SSc have not been previously investigated, and the functional potential of these cells has not been fully evaluated.

The primary aim of this study was to evaluate the numbers of and production of cytokines by Treg cells in patients with SSc, with correlation to activity and/or severity of the disease.

Section snippets

Patients

The study was approved by a local Helsinki Committee. Ten patients with SSc, diagnosed according to 1980 American Rheumatism Association criteria, gave informed consent and were enrolled in the study. A healthy volunteer (control) was matched to every patient by age and gender. Twenty milliliters of peripheral blood were drawn from a patient and a matched control for each single experiment.

Cells

PMBCs were isolated on Lyphoprep (Axis-Shield). CD4+ T cells were isolated by magnetic cell sorting with

Patients

Ten consecutive patients with systemic sclerosis, followed by the rheumatology unit of Bnai Zion Medical Center in Haifa, Israel, gave informed consent and were enrolled to this study in the time period from 12/2008 to 3/2009. All patients fully satisfied the 1980 American Rheumatism Association criteria for systemic sclerosis. The clinical and laboratory characteristics of the patients are shown in Table 1. The activity of SSc was calculated by Valentini Disease Activity Index, and the

Discussion

Treg cells represent up to 10% of the CD4+ T-cell subset in the peripheral blood, with responsibility for the regulation of autoreactive T-cells. Depletion of Treg cells leads to the development of multisystem autoimmune disease in animal models [14]. Decreased numbers or alterations in functional activity of Treg cells have been reported in association with several human chronic inflammatory and autoimmune diseases [2], [3], [4]. As such, the results of this study stand out in demonstrating

Acknowledgments

The authors thank Mrs. Katalin Halasz for her excellent technical assistance and Dr. Neve Tov for his advice on the statistical analysis.

References (21)

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1

These authors contributed equally to the work.

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